Age-Related Macular Degeneration (AMD) is the most common cause of blindness in individuals 50 years of age or older in western cultures. More than 8 million Americans suffer from AMD, and this number is predicted to increase by more than 50% in the next 10 years. Evidence indicates that dysregulation of the complement system plays a role in AMD pathogenesis. Additionally, complement dysregulation has been indicated in other chronic diseases such as atherosclerosis, Alzheimers, diabetic angiopathy, and rheumatoid arthritis. Some studies have found a correlation between cognitive impairment and incidence of AMD. Currently, dry AMD (90% of AMD patients) is untreatable, and wet AMD can be ameliorated by repeated injections of anti-Vascular Endothelial Growth Factor therapeutics. Ocular injections are not free from complication, however, and methods to decrease the frequency of injections are under research. One approach is to deliver DNA that can alter the disease course. Delivery of a complement inhibitor to the cells of the retinal pigment epithelium (RPE) has potential to benefit both wet and dry AMD patients. No preferred method exists among DNA delivery strategies because each method has restrictions. Non- viral methods avoid the dangerous and limiting complications of viral delivery, but are historically less efficient and of shorter duration. Thus, a need exists for the development of an efficient and safe delivery system that enhances longevity of transgene expression. This study proposes to significantly upgrade upon a non-viral delivery system termed POD (Peptide for Ocular Delivery). When pegylated (PEG) and injected subretinally, POD can deliver transgene DNA to RPE cells in vivo. When injected intravenously, PEG-POD delivers transgene DNA systemically to other tissues, especially the lung. However, transgene delivery by PEG-POD is subject to a short duration and entrapment in the lysosomal-endosomal pathway. Thus, the primary goal of this proposal is to enhance the PEG-POD technology such that it can be used to deliver CD59 (a complement inhibitor) expressing plasmids to the RPE for treatment of AMD. The improved POD delivery agent will be validated in an in vivo model of wet AMD. Should POD-delivered complement inhibitors demonstrate efficacy in the wet AMD model, they will have a high therapeutic potential for dry AMD as well. These results will present a novel solution to a common, debilitating disease. The use of non-viral methods in ocular gene-therapy opens many possibilities for long-term protection from not only AMD but other aging diseases of complement dysfunction. ) PUBLIC HEALTH RELEVANCE: Age-Related Macular Degeneration (AMD) is the most common cause of blindness in persons 50 years of age and older in the western world, afflicting more than 8 million Americans. This study will develop a long-lasting and safe approach to treat AMD. Given that the pathogenesis behind AMD is similar in part to other diseases of aging, this study will potentially have applications in the general field of aging.